BioWorld Today Contributor
Alzheimer's is a bleak disease. Its hallmark symptom - inexorable and complete memory loss - is cruel and frightening. It affects an estimated 5 million Americans, and its prevalence is growing as the population ages.
While progress against the disease has been steady, drugs on the market - Neurobiological Technologies Inc.'s Namenda; Pfizer Inc.'s Aricept; Novartis AG's Exelon; First Horizon Pharmaceutical Corp.'s Cognex; and Shire Pharmaceuticals Group plc's Reminyl - ameliorate some of the symptoms of the disease but do not address its underlying neuropathology.
But a new compound might be able to do just that, according to findings published in the July 27, 2004, issue of the Proceedings of the National Academy of Sciences in a paper titled "Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice." It was authored by researchers from NeuroLogic Inc., of Rockville, Md.; the Catholic University of Leuven, Belgium; the University of Illinois at Chicago; and The Blanchette Rockefeller Neurosciences Institute in Morgantown, W. Va. The paper details bryostatin, a compound already in clinical trials as an antitumor agent, and suggests it positively affects the processing of the protein that underlies Alzheimer's neuropathology in vitro and reduces mortality from the disease in a transgenic mouse model.
Amyloid plaques are an important underlying cause of Alzheimer's neuropathology. In fact, while Alzheimer's can be diagnosed with high accuracy based on clinical symptoms, a postmortem brain autopsy to check for plaques remains the only definitive way to confirm the diagnosis (albeit too late to do anybody any good). Amyloid plaques are deposits of amyloid protein that cannot be cleared by the brain's normal metabolic pathways, and, thus, piles up in plaques that then secrete toxins into surrounding brain tissue.
Amyloid plaques result, fittingly enough, from the mis-processing of amyloid precursor protein, or APP. APP is processed by a-, b- and g-secretases. Cut by a-secretase, APP is split into two harmless and, possibly even, beneficial proteins that easily are cleared by the brain's waste-processing mechanisms. Cutting by b-secretase sets in motion processing, which ultimately results in the formation of amyloid plaques. The normal biological functions of amyloid precursor protein are unknown, but it is thought to be involved in plasticity and synaptic remodeling - in other words, learning and memory mechanisms.
The exact factors determining whether APP will be processed for clearance or end up snarling the brain of Alzheimer's disease victims are unknown, but one molecule that regulates APP and can tip the balance in favor of processing by a-secretase is protein kinase C (PKC). That's where the current research comes in.
The Tale Of Transgenic Mice
"It was known that PKC plays a role in normal learning and memory, and that PKC deficiencies are correlated with Alzheimer's disease," said Daniel Alkon, scientific director of the Blanchette institute and senior author of the study. "Therefore, Alzheimer's patients may be more in need of activators of PKC."
Alkon and his collaborators chose to test bryostatin, a known PKC activator already in clinical trials as a cancer therapeutic. The researchers first tested the effect of bryostatin on cultured cell lines taken from Alzheimer's disease patients. Treatment with the drug activated PKC and led to a notable increase in the levels of "good" APPa being secreted by the cell cultures.
Next, the researchers used transgenic mice to test whether bryostatin would be effective in animals, as well as isolated cells. The researchers generated two sets of mice carrying copies of human genes that cause them to overexpress APP. Mice with those genes produce amyloid plaques, and male mice have a high rate of premature death from Alzheimer's.
Alkon and his colleagues found that the premature death rate was markedly attenuated by treatment with bryostatin from an early age. (For unknown reasons and in contrast to humans, while women get worse Alzheimer's than men, female transgenic mice do not show the enhanced death rate, and thus cannot show the reversal by bryostatin.)
The researchers also investigated the behavioral effects of bryostatin treatment. The mice showed no improvement on a learning task after treatment with bryostatin, though they did show less fear in a new situation. However, Alkon said, behavioral studies in rats since have shown a positive effect of bryostatin on learning tasks. Those findings will be published separately in a forthcoming paper.
Bryostatin Might Reduce' Alzheimer's Progress
Bryostatin has an advantage from a drug development standpoint - the compound already is in clinical development as a cancer drug, so safety and toxicity issues have been investigated to some extent. GPC Biotech AG originally received orphan drug designation for bryostatin in combination with Taxol to treat esophageal cancer, but the company announced in March that it was discontinuing that program, citing an inability to find a treatment regimen "that provides sufficient evidence of efficacy combined with an acceptable toxicity profile."
Bryostatin is being studied in combination with other cancer agents in a variety of NCI-sponsored Phase I and II trials.
Alkon said the Blanchette institute, which has taken back most of the patent rights from NeuroLogic, is looking for a corporate alliance to bring bryostatin into clinical trials as an anti-Alzheimer's agent. The institute is in discussions with several potential partners and welcomes additional discussions. He said that, of the drugs approved for Alzheimer's disease, none "have neuroprotection as a goal. They focus on amelioration and their impact is rather modest. This may be the first therapeutic to bring two benefits: ameliorate the symptoms and reduce the progress of the disease. We think that's rather unique."